In This Issue of Diabetes

Mechanistically Oriented Clustering of Type 2 Diabetes Risk Alleles

Data in this issue of Diabetes indicate that many of the five dozen or so known type 2 diabetes risk variants cluster into just four groups that are based
on mechanisms that underpin specific defects common in diabetes. The article by Dimas et al. (p. 2158) builds on findings from a smaller study in which 19 loci were examined in relation to a number of quantitative traits that
are frequently associated with diabetes. The new study—which focuses on quantitative traits in nondiabetic people of European
ancestry—is notable because of the breadth of data upon which the results are based, with basal measures available in up to
58,000 individuals and dynamic measures available from glucose or intravenous glucose tolerance challenges in up to 17,000
individuals. These data were used to examine 14 distinct phenotypes describing traits for a variety of defects that are known
to increase diabetes risk, including fasting glucose and insulin, insulin sensitivity indices, Matsuda index, proinsulin,
glucose uptake, and acute insulin response, among others. Of the 14 traits, 10 were based on sample sizes exceeding 10,000
individuals, and these principal traits were of particular interest in the new study. Initial cluster analyses showed that
the phenotypes grouped together in ways that would be expected based on their relationships to diabetes physiology. Reclustering
of these data with 37 of the established type 2 diabetes susceptibility loci generated four phenotype clusters. Each of these
clusters contained specific susceptibility loci that were associated with the general defect in the cluster (e.g., insulin
resistance, reduced insulin secretion and hyperglycemia, proinsulin processing, and β-cell function). The results of this
new study not only highlight the mechanistic variety susceptibility to diabetes, but they also pave the way for more detailed
explorations aimed at understanding the individual-level risk for diabetes. — Helaine E. Resnick, PhD, MPH

Although the autoimmune nature of type 1 diabetes has fueled an interest in the development of immunomodulatory agents such
as vaccines to prevent or reverse disease, recent trials have not been overwhelmingly positive. In this issue of Diabetes, Pagni et al. (p. 2015) show data that support the use of interleukin-1β (IL-1β) blockade in combination with GAD65 vaccine. In the new report,
mice were assigned one of four treatments: isotype control Ab, anti–IL-1β Ab, GAD65 DNA vaccine in conjunction with isotype
Ab (“isot/GAD treatment”), and GAD65 plus anti–IL-1β Ab. Blood glucose was assessed at multiple time points following 4 weeks
of treatment. At week five, 53% of mice receiving combination therapy (CT) had reverted to euglycemia compared with a 33%
reversal rate among those on isot/GAD treatment. By contrast, anti–IL-1β monotherapy resulted in only 17% of mice returning
to euglycemia, and there was no impact on blood glucose among those on isotype Ab treatment. At 8 weeks’ post-treatment, mean
glucose levels were consistently lower in CT-treated mice, with 43% of this group remaining euglycemic. The authors stress
that mice with glucose between 250 and 400 mg/dL at the beginning of the study had more favorable responses to CT than those
whose levels were over 400 mg/dL, an observation suggesting that a minimal residual β-cell mass is necessary to ensure protection
with this treatment. At 12 weeks, CT-treated mice that did not reach euglycemia maintained glucose levels that were no worse
than baseline, suggesting a decline in disease progression in this group. In addition to improved glycemia, CT was associated
with lower levels of islet infiltration by CD11bhigh cells, which was suggestive of a more favorable immunologic profile. The encouraging outcomes that are highlighted in the
new report may pave the way for further exploration of therapies combining IL-1β blockade with vaccines to specific antigens.
— Wendy Chou, PhD

Caution Urged for HOMA-IR

A new report summarizing data from 36 healthy dogs undergoing diet-induced insulin resistance (IR) not only showed that when
used to quantify IR, the homeostatic model assessment of IR (HOMA-IR) performed poorly relative to both clamp and intravenous
glucose tolerance testing (IVGTT), it also revealed that HOMA-IR actually showed improvements in IR in more than one-third
of the dogs in the study as a result of measurement artifact. The article by Ader et al. in this month’s issue of Diabetes (p. 1914) sheds light on the potentially widespread implications of using HOMA-IR in research settings in which insulin secretion
is either unclear or diminished. After 2–3 weeks of baseline testing, the dogs were fed a high-fat diet over a 6-week period.
At baseline and 6 weeks, the dogs underwent clamps and IVGTT, and HOMA-IR was also calculated from measures of fasting glucose
and insulin. Initial findings indicated a low correlation between baseline HOMA-IR and the other two indices of IR. Although
the high-fat diet resulted in a 7% increase in total adiposity and accompanying increases in IR measured by both clamp and
IVGTT, similar changes were not reflected in HOMA-IR. Although 23 dogs had increases in HOMA-IR that suggested increased IR,
the changes were modest and did not reach statistical significance. Notably, 13 animals had HOMA-IR measures that suggested
decreased IR. The authors stress that changes in HOMA-IR are affected by changes in fasting insulin and glucose, and in the
new experiments, glucose did not change, but there was a slight increase in fasting insulin. Thus, in this setting, HOMA-IR
did not offer meaningful advantages over fasting insulin alone as a surrogate for IR. Additional analyses showed a strong
overall correlation between HOMA-IR and acute insulin response, but HOMA-IR was especially unsuited to estimate insulin sensitivity
in the dogs whose insulin response was at the lower level of the normal range. Taken together, these findings suggest that
using HOMA-IR as a surrogate for IR should be approached with extreme caution, particularly in settings where β-cell function
is unknown. — Helaine E. Resnick, PhD, MPH

An article by Racine et al. in this issue of Diabetes (p. 2051) investigates how hematopoietic cell transplantation (HCT) impacts type 1 diabetes in mice, with a focus on the role of major
histocompatibility complex (MHC)-mismatched mixed chimerism in tolerizing autoreactive B lymphocytes. It is well-known that
MHC plays a significant role in determining an individual’s susceptibility to type 1 diabetes, as well as other autoimmune
disorders. The new study, which builds on previous research by the same group, involved a transplant group that received nonmyeloablative
conditioning and transplantation of donor T-cell–depleted spleen and whole bone marrow cells. The control group received conditioning
only. Induction of mixed chimerism depleted both host/pre-existing and de novo–developed autoreactive B cells, with apoptosis
of splenic T1 B cells markedly greater in chimeras relative to controls. At 60 days after transplantation, serum anti-insulin
autoantibody was undetectable in the transplant group, whereas control mice exhibited significantly higher values. The article
outlines a possible model mechanism by which HCT results in injected donor CD8+ T cells killing nearly all pre-existing host-type B cells, both auto- and nonautoreactive, thereby tolerizing donor CD8+ T cells. The engraftment of B cells establishes a chimeric mix of host and de novo B cells, but the ensuing dominance of
donor B cells comes at the expense of host B-cell apoptosis, undoing the associated autoimmunity of host B cells. Importantly,
this approach deactivates autoimmunity both in autoreactive T cells and autoreactive B cells, and it could be developed as
a novel therapeutic strategy for type 1 diabetes. — Wendy Chou, PhD